{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T16:30:01Z","timestamp":1772814601098,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T00:00:00Z","timestamp":1569542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003157","name":"Myasthenia Gravis Foundation of America","doi-asserted-by":"publisher","award":["FP00094864"],"award-info":[{"award-number":["FP00094864"]}],"id":[{"id":"10.13039\/100003157","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS031744"],"award-info":[{"award-number":["NS031744"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS109491"],"award-info":[{"award-number":["NS109491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To characterize the molecular and phenotypic basis of a severe slow\u2010channel congenital myasthenic syndrome (SCCMS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intracellular and single\u2010channel recordings from patient endplates; alpha\u2010bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 24 variants reported to cause SCCMS only two appear in the AChR \u03b4\u2010subunit. We here report a 16\u2010year\u2010old patient harboring a novel \u03b4L273F mutation (\u03b4L294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR \u03b4 subunit. Kinetic analyses with ACh and the weak agonist choline indicate that \u03b4L273F prolongs the channel opening bursts 9.4\u2010fold due to a 75\u2010fold increase in channel gating efficiency, whereas a previously identified \u03b5L269F mutation (\u03b5L289F in HGVS nomenclature) at an equivalent location in the AChR \u03b5\u2010subunit prolongs channel opening bursts 4.4\u2010fold due to a 30\u2010fold increase in gating efficiency. Structural modeling of AChR predicts that inter\u2010helical hydrophobic interactions between the mutant residue in the \u03b4 and \u03b5 subunit and nearby M2 domain residues in neighboring \u03b1 subunits contribute to structural stability of the open relative to the closed channel states.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The greater increase in gating efficiency by \u03b4L273F than by \u03b5L269F explains why \u03b4L273F has more severe clinical effects. Both \u03b4L273F and \u03b5L269F impair channel gating by disrupting hydrophobic interactions with neighboring \u03b1\u2010subunits. Differences in the extent of impairment of channel gating in \u03b4 and \u03b5 mutant receptors suggest unequal contributions of \u03b5\/\u03b1 and \u03b4\/\u03b1 subunit pairs to gating efficiency.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.50902","type":"journal-article","created":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T10:24:39Z","timestamp":1569579879000},"page":"2066-2078","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Slow\u2010channel myasthenia due to novel mutation in M2 domain of AChR delta subunit"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7087-5166","authenticated-orcid":false,"given":"Xin\u2010Ming","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Neurology and Neuromuscular Research Laboratory Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margherita","family":"Milone","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuromuscular Research Laboratory Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang\u2010Long","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Vesicular Biology Laboratory Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brenda","family":"Banwell","sequence":"additional","affiliation":[{"name":"Division of Neurology Department of Pediatrics Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duygu","family":"Selcen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuromuscular Research Laboratory Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven M.","family":"Sine","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering and Receptor Biology Laboratory Mayo Clinic Rochester Minnesota"},{"name":"Department of Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota"},{"name":"Department of Neurology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew G.","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuromuscular Research Laboratory Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,9,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70201-7"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0955-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201810023"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.3.758"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30383"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-15-05651.1997"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23043"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10077"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-011-6204-9"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.18.10466"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20861"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.9.1217"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.4.1078"},{"key":"e_1_2_8_15_1","first-page":"681","volume-title":"Myology","author":"Engel AG","year":"2004"},{"key":"e_1_2_8_16_1","first-page":"1018","volume-title":"\"Quantitative morphological studies of muscle\". 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